Aldosterone and Cardiovascular Disease: Research and Mentoring Program

醛固酮和心血管疾病：研究和指导计划

• 批准号: 9314760
• 负责人: Gail Kurr Adler
• 金额: $ 12.15万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-02 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314760
• 关键词: Address; Aldosterone; Anti-Retroviral Agents; Applications Grants; Area; Atherosclerosis; Biological Markers; Biology; Blood Vessels; CCL2 gene; Cardiac; Cardiomyopathies; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular system; Clinical Investigator; Complement; Coronary; Data; Diabetes Mellitus; Disease; Double-Blind Method; Educational process of instructing; FDA approved; Fibrosis; Functional disorder; Funding; Galectin 3; Generations; Grant; HIV; Heart Diseases; High Prevalence; Hormones; IL6 gene; Image; Imaging Techniques; Imaging technology; Immunologic Markers; Impairment; Individual; Inflammation; Inflammation Mediators; Injury; Insulin Resistance; Investigation; LCN2 gene; Link; Magnetic Resonance Imaging; Measures; Mentors; Metabolic; Metabolic Diseases; Mineralocorticoid Receptor; Modeling; Morbidity - disease rate; Morphology; Myocardial; Myocarditis; Obesity; Outcome; Pathologic; Patients; Pharmaceutical Preparations; Physicians; Placebos; Plasma; Population; Positron-Emission Tomography; Radiology Specialty; Randomized; Receptor Activation; Renin; Renin-Angiotensin-Aldosterone System; Research; Research Personnel; Risk; Risk Factors; Risk Reduction; Role; Sum; Techniques; Testing; Time; Training; Training Support; Vascular Diseases; Visceral; antiretroviral therapy; burden of illness; cardiotrophin 1; cardiovascular disorder risk; cardiovascular imaging; cardiovascular injury; cardiovascular risk factor; coronary computed tomography angiography; coronary fibrosis; diabetes control; disorder risk; double-blind placebo controlled trial; effective therapy; eplerenone; experience; extracellular; high risk; immune activation; improved; indexing; inflammatory marker; insight; interest; mortality; multidisciplinary; novel; patient oriented; patient oriented research; procollagen Type III-N-terminal peptide; programs; randomized placebo controlled trial; treatment strategy; vascular inflammation; virology

PROJECT SUMMARY/ABSTRACT This K24 competitive renewal application is to provide support for protected time for: 1) my mentoring and teaching of junior clinical investigators; and 2) patient-oriented research investigating the role of aldosterone and the mineralocorticoid receptor (MR) in the pathophysiology of cardiovascular (CV) disease. Aldosterone activates the MR and can cause vascular and cardiac inflammation and fibrosis. With support from the first five years of K24 funding, we showed that, in individuals with well-controlled diabetes, treatment with a MR antagonist improves coronary flow reserve, a measure of coronary vascular function. In these same individuals, elevated aldosterone levels were associated with increases in myocardial extracellular volume (ECV), a measure of cardiac inflammation and fibrosis. These findings suggest that, in diabetes, MR activation contributes to impaired coronary flow reserve and increased myocardial ECV; both of which predict increased CV morbidity and mortality in diabetes. In addition, our preliminary data indicates that individuals with metabolic disturbances, increased visceral adiposity and insulin resistance, and HIV have elevated aldosterone levels. Individuals with HIV, well-treated with antiretroviral therapy, have impaired coronary flow reserve, increased myocardial ECV, and increased coronary plaque. They are at increased risk of CV disease as compared to non-HIV individuals. This increased risk of CV disease cannot be accounted for by traditional CV risk factors and no successful treatment strategies exist to complement antiretroviral therapy to reduce CVD risk in HIV. This proposal tests the hypothesis that excess MR activity leads to coronary vascular dysfunction, myocardial inflammation and fibrosis, and increased coronary plaque in HIV. Thus, we will perform a randomized, double blind, placebo controlled trial to demonstrate that treatment with a selective MR antagonist, eplerenone, for 12 months improves coronary flow reserve (Specific Aim 1), myocardial ECV (Specific Aim 2) and coronary plaque (Specific Aim 3). We will utilize sophisticated radiologic techniques (cardiac PET, cardiac MRI and coronary CTA) to quantify these CV outcomes. This research, which is the first comprehensive investigation of MR blockade on CV disease in HIV, aims to provide novel mechanistic insights and a promising strategy for CVD risk reduction in HIV. Moreover, these data should provide critical insight for other non-HIV populations with increased CVD burden. These studies will provide a fertile area for investigation by trainees interested in patient-oriented research and in identifying new, effective treatments of cardiovascular disease in patients with metabolic disorders.

项目摘要/摘要 此K24竞争性更新应用程序是为受保护的时间提供支持：1）我的指导和 初级临床研究人员的教学； 2）研究醛固酮作用的患者研究 以及心血管（CV）疾病的病理生理学中的盐皮质激素受体（MR）。 醛固酮激活MR并可能引起血管和心脏炎症和纤维化。在来自 K24资金的前五年，我们表明，在控制良好的糖尿病患者中 MR拮抗剂改善了冠状动脉流量储备，这是冠状动脉血管功能的量度。在这些 个体，醛固酮水平升高与心肌外体积增加有关 （ECV），一种心脏炎症和纤维化的量度。这些发现表明，在糖尿病中，MR激活 有助于冠状动脉流量储备和心肌ECV增加；两者都预测增加 糖尿病的CV发病率和死亡率。此外，我们的初步数据表明 代谢障碍，内脏肥胖和胰岛素抵抗的增加，HIV具有升高的醛固酮 水平。患有抗逆转录病毒疗法的艾滋病毒的人患有冠状动脉流量储备， 增加心肌ECV并增加冠状动脉斑块。他们患有简历疾病的风险增加 与非HIV个体相比。传统简历无法解释这种CV疾病的风险增加 危险因素和没有成功的治疗策略来补充抗逆转录病毒疗法以减少CVD 艾滋病毒的风险。该建议检验了以下假设：过量的MR活性导致冠状动脉血管功能障碍， 心肌炎症和纤维化，并增加了HIV中的冠状动脉斑块。因此，我们将执行 随机，双盲，安慰剂对照试验，以证明选择性MR的治疗 拮抗剂，eplerenone，12个月改善了冠状动脉流动储备（特定目标1），心肌ECV （特定目标2）和冠状动脉斑块（特定目标3）。我们将利用复杂的放射学技术 （心脏宠物，心脏MRI和冠状动脉CTA）量化这些CV结果。 这项研究是对艾滋病毒CV疾病MR封锁的首次全面研究，旨在 提供新颖的机械洞察力和艾滋病毒中CVD风险降低的有前途的策略。而且，这些 数据应为CVD负担增加的其他非HIV人群提供关键见解。这些研究 将为对患者研究感兴趣的受训者提供一个肥沃的领域，并确定 代谢性疾病患者心血管疾病的新有效治疗。